Gonadal hormones and stroke risk: PCOS as a case study.

It is well known that stroke incidence and outcome is sex-dependent and influenced by age and gonadal hormones. In post-menopausal and/or aged females, declining estrogen levels increases stroke risk. However, women who experience early menopause also have an increase in stroke risk. This suggests that, regardless of age, gonadal hormones regulate stroke risk and severity. This review discusses prolonged gonadal hormone dysfunction in a common female endocrine disorder known as polycystic ovarian syndrome, PCOS, and the associated increased risk of stroke due to resulting hyperandrogenism and metabolic comorbidities.

Association of ovarian hormones with mapping concept of self and others in the brain's default mode network.

The brain's default mode network (DMN) has become closely associated with self-referential mental activity, particularly in the resting-state. Prior reports point that the sex hormones are potent modulators of brain plasticity and functional connectivity. However, it is uncertain whether changes in ovarian hormones, as occur during the monthly menstrual cycle, substantially affects the functional connectivity of DMN. Here, we employed a Self-Awareness Scale (SAS) and the resting-state functional MRI in the late follicular phase and the mid-luteal phase to investigate the effect of the estradiol (E2) and progesterone on the SAS and DMN. On the behavioral level, increased progesterone facilitated women's other-focused attention. The regions of interest-based resting-state functional connectivity analyses continued to demonstrate a negative correlation of the relative progesterone and the medial prefrontal cortex-inferior temporal gyrus (mPFC-ITG) functional connectivity, and a facilitated effect of relative E2 on the mPFC-inferior parietal lobule functional connectivity in the DMN. Furthermore, as a core hub of the 'theory of mind', the functional connectivity between the ITG and thalamus was found negatively correlated with the relative E2. Meanwhile, the mid-luteal phase, which had significantly lower relative E2 levels, was indicated had stronger ITG-thalamus functional connectivity during the resting state. These results demonstrated an opposite effect of E2 and progesterone on the DMN and the other-focused preference in the mid-luteal phase, extended previous evidence of the potentially adaptive psychological effects of ovarian hormones on mapping self and others in the brain networks.

In vivo magnetic resonance imaging reveals the effect of gonadal hormones on morphological and functional brain sexual dimorphisms in adult sheep.

Sex differences in the brain and behavior are produced by the perinatal action of testosterone, which is converted into estradiol by the enzyme aromatase in the brain. Although magnetic resonance imaging (MRI) has been widely used in humans to study these differences, the use of animal models, where hormonal status can be properly manipulated, is necessary to explore the mechanisms involved. We used sheep, a recognized model in the field of neuroendocrinology, to assess brain morphological and functional sex differences and their regulation by adult gonadal hormones. To this end, we performed voxel-based morphometry and a resting-state functional MRI approach to assess sex differences in gonadally intact animals. We demonstrated significant sex differences in gray matter concentration (GMC) at the level of the gonadotropic axis, i.e., not only within the hypothalamus and pituitary but also within the hippocampus and the amygdala of intact animals. We then performed the same analysis one month after gonadectomy and found that some of these differences were reduced, especially in the hypothalamus and amygdala. By contrast, we found few differences in the organization of the functional connectome between males and females either before or after gonadectomy. As a whole, our study identifies brain regions that are sexually dimorphic in the sheep brain at the resolution of the MRI and highlights the role of gonadal hormones in the maintenance of these differences.

Gonadal hormone-dependent vs. -independent effects of kisspeptin signaling in the control of body weight and metabolic homeostasis.

BACKGROUND: Kisspeptins, encoded by Kiss1, have emerged as essential regulators of puberty and reproduction by primarily acting on GnRH neurons, via their canonical receptor, Gpr54. Mounting, as yet fragmentary, evidence strongly suggests that kisspeptin signaling may also participate in the control of key aspects of body energy and metabolic homeostasis. However, characterization of such metabolic dimension of kisspeptins remains uncomplete, without an unambiguous discrimination between the primary metabolic actions of kisspeptins vs. those derived from their ability to stimulate the secretion of gonadal hormones, which have distinct metabolic actions on their own. In this work, we aimed to tease apart primary vs. secondary effects of kisspeptins in the control of key aspects of metabolic homeostasis using genetic models of impaired kisspeptin signaling and/or gonadal hormone status. METHODS: Body weight (BW) gain and composition, food intake and key metabolic parameters, including glucose tolerance, were comparatively analyzed, in lean and obesogenic conditions, in mice lacking kisspeptin signaling due to global inactivation of Gpr54 (displaying profound hypogonadism; Gpr54-/-) vs. Gpr54 null mice with selective re-introduction of Gpr54 expression only in GnRH cells (Gpr54-/-Tg), where kisspeptin signaling elsewhere than in GnRH neurons is ablated but gonadal function is preserved. RESULTS: In male mice, global elimination of kisspeptin signaling resulted in decreased BW, feeding suppression and increased adiposity, without overt changes in glucose tolerance, whereas Gpr54-/- female mice displayed enhanced BW gain at adulthood, increased adiposity and perturbed glucose tolerance, despite reduced food intake. Gpr54-/-Tg rescued mice showed altered postnatal BW gain in males and mildly perturbed glucose tolerance in females, with intermediate phenotypes between control and global KO animals. Yet, body composition and leptin levels were similar to controls in gonadal-rescued mice. Exposure to obesogenic insults, such as high fat diet (HFD), resulted in exaggerated BW gain and adiposity in global Gpr54-/- mice of both sexes, and worsening of glucose tolerance, especially in females. Yet, while rescued Gpr54-/-Tg males displayed intermediate BW gain and feeding profiles and impaired glucose tolerance, rescued Gpr54-/-Tg females behaved as controls, except for a modest deterioration of glucose tolerance after ovariectomy. CONCLUSION: Our data support a global role of kisspeptin signaling in the control of body weight and metabolic homeostasis, with a dominant contribution of gonadal hormone-dependent actions. However, our results document also discernible primary effects of kisspeptin signaling in the regulation of body weight gain, feeding and responses to obesogenic insults, which occur in a sexually-dimorphic manner. SUMMARY OF TRANSLATIONAL RELEVANCE: Kisspeptins, master regulators of reproduction, may also participate in the control of key aspects of body energy and metabolic homeostasis; yet, the nature of such metabolic actions remains debatable, due in part to the fact that kisspeptins modulate gonadal hormones, which have metabolic actions on their own. By comparing the metabolic profiles of two mouse models with genetic inactivation of kisspeptin signaling but different gonadal status (hypogonadal vs. preserved gonadal function), we provide herein a systematic dissection of gonadal-dependent vs. -independent metabolic actions of kisspeptins. Our data support a global role of kisspeptin signaling in the control of body weight and metabolic homeostasis, with a dominant contribution of gonadal hormone-dependent actions. However, our results document also discernible primary effects of kisspeptin signaling in the regulation of body weight gain, feeding and responses to obesogenic insults, which occur in a sexually-dimorphic manner. These data pave the way for future analyses addressing the eventual contribution of altered kisspeptin signaling in the development of metabolic alterations, especially in conditions linked to reproductive dysfunction.

Gonadal hormone fluctuations do not affect the expression or extinction of fear-potentiated startle in female rats.

Prior studies suggest that levels of ovarian hormones may affect learning and memory in rats, including studies of fear conditioning and extinction. We previously showed that female rats show reduced retention of extinction compared to males when measuring fear-potentiated startle, but not when measuring freezing behavior. One commonly reported observation in studies of freezing behavior is that rats with increased levels of estradiol during extinction learning show better retention of extinction than rats given extinction training when levels of estradiol are low. Here, we tested the hypothesis that fear extinction retention in a fear-potentiated startle paradigm in females is influenced by levels gonadal hormones, which we had not accounted for in our original report. We used the fear-potentiated startle paradigm to test if extinction learning was affected by estrous phase, ovariectomy, or acute systemic injections of estradiol in ovariectomized rats. We report that neither the expression nor extinction of fear-potentiated startle differed in rats given extinction training in proestrus compared to those in metestrus. Removal of the ovaries had no effect on fear acquisition or extinction learning as assessed by fear-potentiated startle. Finally, systemic injections of estradiol given to ovariectomized rats before extinction training had no effect on the expression of fear or the retention of extinction. Our findings suggest that the effect of female gonadal hormones on fear conditioning and extinction may depend on the measure of fear employed or by the parameters used to study fear learning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The role of gonadal hormones in the hypoglossal discharge activity of rats exposed to chronic intermittent hypoxia.

OBJECTIVE: The role of gonadal hormones in chronic intermittent hypoxia (CIH)-evoked hypoglossal nerve (XII) neuroplasticity has not been thoroughly studied. The purpose of this study was to reveal the effects of gonadal hormone concentration variations on the XII discharge activity of rats exposed to CIH and the corresponding relationship with 5-hydroxytryptamine (5-HT). METHODS: This study employed five groups of female rats and six groups of male rats. Gonadal hormone levels were modified through gonadal resection and daily supplementation with gonadal hormones in rats of both sexes. Rats in the CIH groups were exposed to an additional 4 weeks of CIH once the operative incision for gonadectomy had healed. Finally, XII spontaneous discharge activities were recorded, and serum estradiol, testosterone and 5-HT concentrations were detected by ELISA. RESULTS: Among the female rats, the normal estradiol level groups expressed XII neuroplasticity, while the low estradiol level group failed to express this phenomenon. XII neuroplasticity was related to the serum estradiol concentration. In the male rats, XII neuroplasticity was successfully evoked in the normal testosterone level group but was suppressed in the low testosterone level group and aromatase inhibitor group. XII neuroplasticity was not significantly related to serum testosterone concentrations. Both estradiol and testosterone concentrations were related to 5-HT concentrations. CONCLUSIONS: This is the first study to analyze the effects of gonadal hormones on XII neuroplasticity in both female and male rats. The results suggest that the estradiol level is related to XII neuroplasticity rather than the testosterone level, and testosterone may indirectly adjust XII neuroplasticity by converting to estradiol. Estradiol and testosterone levels are related to 5-HT levels in the respective genders.

Characterization and gonadal hormone regulation of a sexually dimorphic corticotropin-releasing factor receptor 1 cell group.

Corticotropin-releasing factor binds with high affinity to CRF receptor 1 (CRFR1) and is implicated in stress-related mood disorders such as anxiety and depression. Using a validated CRFR1-green fluorescent protein (GFP) reporter mouse, our laboratory recently discovered a nucleus of CRFR1 expressing cells that is prominent in the female rostral anteroventral periventricular nucleus (AVPV/PeN), but largely absent in males. This sex difference is present in the early postnatal period and remains dimorphic into adulthood. The present investigation sought to characterize the chemical composition and gonadal hormone regulation of these sexually dimorphic CRFR1 cells using immunohistochemical procedures. We report that CRFR1-GFP-ir cells within the female AVPV/PeN are largely distinct from other dimorphic cell populations (kisspeptin, tyrosine hydroxylase). However, CRFR1-GFP-ir cells within the AVPV/PeN highly co-express estrogen receptor alpha as well as glucocorticoid receptor. A single injection of testosterone propionate or estradiol benzoate on the day of birth completely eliminates the AVPV/PeN sex difference, whereas adult gonadectomy has no effect on CRFR1-GFP cell number. These results indicate that the AVPV/PeN CRFR1 is regulated by perinatal but not adult gonadal hormones. Finally, female AVPV/PeN CRFR1-GFP-ir cells are activated following an acute 30-min restraint stress, as assessed by co-localization of CRFR1-GFP cells with phosphorylated (p) CREB. CRFR1-GFP/pCREB cells were largely absent in the male AVPV/PeN. Together, these data indicate a stress and gonadal hormone responsive nucleus that is unique to females and may contribute to sex-specific stress responses.

Menstrual cycle irregularity and menopause status influence cognition in women with schizophrenia.

Cognitive impairments are a core feature of schizophrenia and contribute significantly to functional complications. Current pharmacological treatments do not ameliorate cognitive dysfunction and the aetiology of cognitive impairments are poorly understood. Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain and have been suggested to also influence cognition. The aim of the current study was to investigate how HPG axis hormones effect cognition, specifically exploring the influence of menopause status and menstrual cycle irregularity on cognitive performance in women with schizophrenia. The data for the present study represents pooled baseline data from three clinical trials. Two hundred and forty female participants with a diagnosis of schizophrenia or schizoaffective disorder were included in the analysis. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status. Hormone assays for serum sex steroids and pituitary hormones (including estradiol, progesterone, luteinising hormone and follicle-stimulating hormone) were conducted and women were classified as postmenopausal; perimenopausal; premenopausal/reproductive, further classified into regular and irregular menstrual cycles. To model a comparison of cognitive performance for i) perimenopausal; ii) post-menopausal women and iii) reproductive aged women with irregular cycles to reproductive aged women with regular cycles a semiparametric regression model (generalised additive mode) was fitted. The results revealed that in females with schizophrenia, menstrual cycle irregularity predicted significantly poorer cognitive performance in the areas of psychomotor speed, verbal fluency and verbal memory. Perimenopause was not associated with cognitive changes and the post-menopausal period was associated with poorer visuospatial performance. This study provides evidence to associate reproductive hormones with cognitive dysfunction in schizophrenia.

The neuroendocrinology of sexual attraction.

Sexual attraction has two components: Emission of sexually attractive stimuli and responsiveness to these stimuli. In rodents, olfactory stimuli are necessary but not sufficient for attraction. We argue that body odors are far superior to odors from excreta (urine, feces) as sexual attractants. Body odors are produced by sebaceous glands all over the body surface and in specialized glands. In primates, visual stimuli, for example the sexual skin, are more important than olfactory. The role of gonadal hormones for the production of and responsiveness to odorants is well established. Both the androgen and the estrogen receptor α are important in male as well as in female rodents. Also in primates, gonadal hormones are necessary for the responsiveness to sexual attractants. In males, the androgen receptor is sufficient for sustaining responsiveness. In female non-human primates, estrogens are needed, whereas androgens seem to contribute to responsiveness in women.

Olfactory conditioned same-sex partner preference in female rats: Role of ovarian hormones.

The dopamine D2-type receptor agonist quinpirole (QNP) facilitates the development of conditioned same-sex partner preference in males during cohabitation, but not in ovariectomized (OVX) females, primed with estradiol benzoate (EB) and progesterone (P). Herein we tested the effects of QNP on OVX, EB-only primed females. Females received a systemic injection (every four days) of either saline (Saline-conditioned) or QNP (QNP-conditioned) and then cohabited for 24h with lemon-scented stimulus females (CS+), during three trials. In test 1 (female-female) preference was QNP-free, and females chose between the CS+ female and a novel female. In test 2 (male-female) they chose between the CS+ female and a sexually experienced male. In test 1 Saline-conditioned females displayed more hops & darts towards the novel female, but QNP-conditioned females displayed more sexual solicitations towards the CS+ female. In test 2 Saline-conditioned females displayed a clear preference for the male, whereas QNP-conditioned females displayed what we considered a bisexual preference. We discuss the effect of dopamine and ovarian hormones on the development of olfactory conditioned same-sex preference in females.

The body has a brake: micrin is a postulated new gonadal hormone curbing tissue overgrowth and restricting reproduction.

There is evidence for an unrecognised classical hormone secreted by the mammalian gonad. This postulated hormone--'micrin' (pronounced 'my-crin')--represents the body's brake against tissue overgrowth. When oestrogens are administered in high doses to female rats there is a considerable (non-artefactual) increase in the relative size and weight of organs such as the pituitary, adrenals, uterus and liver--suggesting an organotrophic (organ-building) role for endogenous oestrogens. This effect is exaggerated if the animals are first ovariectomized, indicating the removal of a negative ovarian factor, micrin. These organ enlargements can be reduced by pretreating the rats with large doses of antioestrogens such as clomiphene and tamoxifen. This antiestrogenic blockade of exogenous oestrogens is itself blunted by prior removal of the ovaries. It is proposed that antioestrogens (e.g. tamoxifen in breast cancer treatment) antagonize the organotrophic effects of oestrogens by competing for the oestrogen receptor peripherally and centrally and via an increase in the secretion of ovarian micrin. It is deduced that micrin is the testicular 'inhibin' proposed in the 1930s, not the molecule that now bears that name, which acts at the pituitary tier as a downregulator of follicle-stimulating hormone. The hallmark of micrin deficiency in the male rat is a pituitary hypertrophy that follows castration. This is reversible with a steroid-depleted aqueous bovine testicular extract, the micrin within which suppresses the hypothalamus, normalizing the pituitary. Micrin probably acts as a brake on peripheral tissues directly but also indirectly at the meta-level via the hypothalamic-pituitary axis, resetting a hypothalamic 'organostat' controlling organ and tissue masses, part of the 'organotrophic system' of internal size regulation. Besides endocrine (circulating) micrin from the gonads there is probably paracrine (locally acting) micrin produced in the brain. This is involved in a somatic cueing system for puberty: the brake comes off at an appropriate body tissue mass disinhibiting the hypothalamus and accelerating the organism towards sexual maturity and full adult stature. This suggests the use in reproductive disorders of micrin-related drugs. These could also be inhibitors of breast, prostate and other cancers, while protecting the bone marrow via a trophic effect on the adrenals (the lack of which protection causes lethal bone marrow depression in oestrogen-treated ferrets and dogs). Benign prostatic hyperplasia is asserted to be a micrin deficiency disorder, involving insufficiently opposed androgen. The rise in cancers with age could be associated with a reduction in micrin protection and a relative lack of this hormone could partly explain why men die younger than women. Micrin is dissimilar in activity to any known molecule and could usefully be isolated, characterised and exploited therapeutically.

Novel aspects of the endocrinology of the menstrual cycle.

Ovarian control of gonadotrophin secretion is normally achieved via the feedback mechanisms mediated by oestradiol and progesterone. Evidence has been provided that nonsteroidal substances, such as inhibin A and B, participate in the negative feedback control of FSH secretion. Another nonsteroidal ovarian substance is gonadotrophin surge-attenuating factor (GnSAF), the activity of which is particularly evident in women undergoing ovulation induction. Accumulating evidence has suggested that GnSAF plays a physiological role during the menstrual cycle. In particular, this factor antagonizes the sensitizing effect of oestradiol on the pituitary response to gonadotrophin-releasing hormone during the follicular phase of the cycle. A hypothesis has been developed that, in the late follicular phase, the activity of GnSAF is reduced and this facilitates the sensitizing effect of oestradiol on the pituitary, thus enforcing the massive discharge of gonadotrophins at the midcycle LH surge. The interaction of oestradiol, progesterone and GnSAF on the hypothalamic-pituitary system provides a novel approach to explain the mechanisms which control LH secretion during the normal menstrual cycle. The ovarian control of gonadotrophin secretion during the normal menstrual cycle is achieved via negative and positive feedback mechanisms. The steroids oestradiol and progesterone are the main regulators; however, nonsteroidal substances, such as inhibin A and inhibn B, also participate. Accumulating evidence has demonstrated that another nonsteroidal ovarian substance, gonadotrophin surge-attenuating factor (GnSAF), plays a key role in the control of LH secretion during the follicular phase and at midcycle, providing thus a novel aspect in the ovarian control of gonadotrophin secretion during the human menstrual cycle. The ovarian control of gonadotrophin secretion during the normal menstrual cycle is achieved via negative and positive feedback mechanisms. The steroids oestradiol and progesterone are the main regulators; however, nonsteroidal substances, such as inhibin A and inhibn B, also participate. Accumulating evidence has demonstrated that another nonsteroidal ovarian substance, gonadotrophin surge-attenuating factor (GnSAF), plays a key role in the control of LH secretion during the follicular phase and at midcycle, providing thus a novel aspect in the ovarian control of gonadotrophin secretion during the human menstrual cycle.

Adaptation to short photoperiods augments circadian food anticipatory activity in Siberian hamsters.

This article is part of a Special Issue "Energy Balance". Both the light-dark cycle and the timing of food intake can entrain circadian rhythms. Entrainment to food is mediated by a food entrainable circadian oscillator (FEO) that is formally and mechanistically separable from the hypothalamic light-entrainable oscillator. This experiment examined whether seasonal changes in day length affect the function of the FEO in male Siberian hamsters (Phodopus sungorus). Hamsters housed in long (LD; 15 h light/day) or short (SD; 9h light/day) photoperiods were subjected to a timed-feeding schedule for 10 days, during which food was available only during a 5h interval of the light phase. Running wheel activity occurring within a 3h window immediately prior to actual or anticipated food delivery was operationally-defined as food anticipatory activity (FAA). After the timed-feeding interval, hamsters were fed ad libitum, and FAA was assessed 2 and 7 days later via probe trials of total food deprivation. During timed-feeding, all hamsters exhibited increases FAA, but FAA emerged more rapidly in SD; in probe trials, FAA was greater in magnitude and persistence in SD. Gonadectomy in LD did not induce the SD-like FAA phenotype, indicating that withdrawal of gonadal hormones is not sufficient to mediate the effects of photoperiod on FAA. Entrainment of the circadian system to light markedly affects the functional output of the FEO via gonadal hormone-independent mechanisms. Rapid emergence and persistent expression of FAA in SD may reflect a seasonal adaptation that directs behavior toward sources of nutrition with high temporal precision at times of year when food is scarce.

Gonadal hormones differently modulate cutaneous wound healing of chronically stressed mice.

Gonadal hormones influence physiological responses to stress and cutaneous wound healing. The aim of this study was to investigate the role of gonadal hormones on cutaneous wound healing in chronically stressed mice. Male and female mice were gonadectomized, and after 25 days, they were spun daily at 115 rpm for 15 min every hour until euthanasia. Twenty-eight days after the gonadectomy, an excisional lesion was created. The animals were killed 7 or 14 days after wounding, and the lesions were collected. Myofibroblast density, macrophage number, catecholamine level, collagen deposition, and blood vessel number were evaluated. In the intact and gonadectomized groups, stress increased the plasma catecholamine levels in both genders. In intact groups, stress impaired wound contraction and re-epithelialization and increased the macrophage number in males but not in females. In addition, stress compromised myofibroblastic differentiation and blood vessel formation and decreased collagen deposition in males but not in females. In contrast to intact mice, wound healing in ovariectomized female mice was affected by stress, while wound healing in castrated male mice was not. In conclusion, gender differences contribute to the cutaneous wound healing of chronically stressed mice. In addition, androgens contribute to the stress-induced impairment of the healing of cutaneous wounds but estrogens inhibit it.

Puberty and adolescence as a time of vulnerability to stressors that alter neurobehavioral processes.

Puberty and adolescence are major life transitions during which an individual's physiology and behavior changes from that of a juvenile to that of an adult. Here we review studies documenting the effects of stressors during pubertal and adolescent development on the adult brain and behavior. The experience of complex or compound stressors during puberty/adolescence generally increases stress reactivity, increases anxiety and depression, and decreases cognitive performance in adulthood. These behavioral changes correlate with decreased hippocampal volumes and alterations in neural plasticity. Moreover, stressful experiences during puberty disrupt behavioral responses to gonadal hormones both in sexual performance and on cognition and emotionality. These behavioral changes correlate with altered estrogen receptor densities in some estrogen-concentrating brain areas, suggesting a remodeling of the brain's response to hormones. A hypothesis is presented that activation of the immune system results in chronic neuroinflammation that may mediate the alterations of hormone-modulated behaviors in adulthood.

Sexual hormones modulate compensatory renal growth and function / Las hormonas sexuales modulan el crecimiento renal compensador (CRC) y la función renal en la uninefrectomía (uNx)

The role played by sexual hormones and vasoactive substances in the compensatory renal growth (CRG) that follows uninephrectomy (uNx) is still controversial. Intact and gonadectomized adult Wistar rats of both sexes, with and without uNx, performed at 90 days age, were studied at age 150 days. Daily urine volume, electrolyte excretion and kallikrein activity (UKa) were determined. Afterwards, glomerular filtration rate and blood pressure were measured, the kidneys weighed and DNA, protein and RNA studied to determine nuclei content and cell size. When the remnant kidney weight at age 150 days was compared with the weight of the kidney removed at the time of uNx, male uNx rats showed the greatest CRG (50%) while growth in the other uNx groups was 25%, 15% and 19% in orchidectomized, female and ovariectomized rats, respectively. The small CRG observed in the uNx female rats was accompanied by the lowest glomerular filtration value, 0.56 ± 0.02 ml/min/g kwt compared, with the other uNx groups, p < 0.05. Cell size (protein or RNA/DNA) was similar for all the groups except for uNx orchidectomized rats. In this group the cytoplasmatic protein or RNA content was lower than in the other groups while DNA (nuclei content) was similar. Some degree of hyperplasia was determined by DNA content in the uNx groups. Male sexual hormones positively influenced CRG and its absence modulated cell size. Female sexual hormones, instead, did not appear to stimulate CRG. The kallikrein kinin system may not be involved in CRG.

La importancia que pueden tener las hormonas sexuales y sustancias vasoactivas sobre el crecimiento renal compensador (CRC) que sigue a la uninefrectomía es aún materia de debate. Se estudiaron ratas Wistar de ambos sexos, a los 150 días de vida, intactas y gonadectomizadas con y sin uNx, realizada a los 90 días de vida. Se midió volumen urinario diario y excreción de electrolitos y actividad de kalikreína urinaria. Se midió filtrado glomerular y presión arterial media extrayéndose luego los riñones que fueron pesados y preparados para estudios histológicos y determinación de ADN, ARN y proteínas para estimar contenido nuclear y tamaño celular. El CRC fue calculado comparando el peso del riñón al momento de las uNx (90 dias de vida) con aquel obtenido a los 150 días de vida. En las ratas macho uNx se observó el mayor CRC (50%) mientras que, en los otros grupos uNx solo alcanzó un 25%, 15% y 19%. El filtrado glomerular acompañó los cambios morfológicos observándose el menor filtrado en las ratas hembras uNx respecto al resto de los grupos 0.56 ± 0.02, p < 0.05. El tamaño celular (proteína o ARN/ ADN) fue similar para todos los grupos excepto para los orquidectomizados uNx, cuyo contenido citoplasmático fue menor. El contenido nuclear (ADN) fue semejante en todos los grupos. Se observó que el CRC está influenciado positivamente por las hormonas sexuales masculinas y su ausencia modula el tamaño celular. La falta de hormonas sexuales femeninas, en cambio, afecta negativamente el CRC. El sistema kalikreína kinina no parecería estar involucrado en el CRC.

Puberty and gonadal hormones: role in adolescent-typical behavioral alterations.

This article is part of a Special Issue "Puberty and Adolescence". Adolescence is characterized by a variety of behavioral alterations, including elevations in novelty-seeking and experimentation with alcohol and other drugs of abuse. Some adolescent-typical neurobehavioral alterations may depend upon pubertal rises in gonadal hormones, whereas others may be unrelated to puberty. Using a variety of approaches, studies in laboratory animals have not revealed clear relationships between pubertal-related changes and adolescent- or adult-typical behaviors that are not strongly sexually dimorphic. Data reviewed suggest surprisingly modest influences of gonadal hormones on alcohol intake, alcohol preference and novelty-directed behaviors. Gonadectomy in males (but not females) increased ethanol intake in adulthood following surgery either pre-pubertally or in adulthood, with these increases in intake largely reversed by testosterone replacement in adulthood, supporting an activational role of androgens in moderating ethanol intake in males. In contrast, neither pre-pubertal nor adult gonadectomy influenced sensitivity to the social inhibitory or aversive effects of ethanol when indexed via conditioned taste aversions, although gonadectomy at either age altered the microstructure of social behavior of both males and females. Unexpectedly, the pre-pubertal surgical manipulation process itself was found to increase later ethanol intake, decrease sensitivity to ethanol's social inhibitory effects, attenuate novelty-directed behavior and lower social motivation, with gonadal hormones being necessary for these long-lasting effects of early surgical perturbations.

Enduring influence of pubertal stressors on behavioral response to hormones in female mice.

This article is part of a Special Issue "Puberty and Adolescence". The pubertal period is a time of change in an animal's response to stress, and it is a second period of sexual differentiation of the brain. Recently, it was discovered that particular stressors during the prolonged pubertal period of female mice result in enduring changes in behavioral responsiveness of the brain to estradiol and progesterone. Depending on the behavior, pubertal immune challenge or shipping from suppliers may decrease, eliminate, or even reverse the effects of estradiol. Pubertal immune challenge results in changes in the number of estrogen receptor-immunoreactive cells in key brain areas suggesting a cellular mechanism for this remodeling of the brain's response to hormones. A hypothesis is put forward that predicts that particular adverse experiences in girls may cause long-term alterations in the brain's response to estradiol and/or progesterone via activation of the immune system. This could lead to mood disorders or altered response to any behavior influenced by estradiol in humans.

Gonadal hormones and the control of reactive gliosis.

Astrocytes and microglia respond to central nervous system (CNS) injury with changes in morphology, proliferation, migration and expression of inflammatory regulators. This phenomenon is known as reactive gliosis. Activation of astrocytes and microglia after acute neural insults, such as stroke or traumatic CNS injury, is considered to be an adaptive response that contributes to minimize neuronal damage. However, reactive gliosis may amplify CNS damage under chronic neurodegenerative conditions. Progesterone, estradiol and testosterone have been shown to control reactive gliosis in different models of CNS injury, modifying the number of reactive astrocytes and reactive microglia and the expression of anti-inflammatory and proinflammatory mediators. The actions of gonadal hormones on reactive gliosis involve different mechanisms, including the modulation of the activity of steroid receptors, such as estrogen receptors α and ß, the regulation of nuclear factor-κB mediated transcription of inflammatory molecules and the recruitment of the transcriptional corepressor c-terminal binding protein to proinflammatory promoters. In addition, the Parkinson's disease related gene parkin and the endocannabinoid system also participate in the regulation of reactive gliosis by estradiol. The control exerted by gonadal hormones on reactive gliosis may affect the response of neural tissue to trauma and neurodegeneration and may contribute to sex differences in the manifestation of neurodegenerative diseases. However, the precise functional consequences of the regulation of reactive gliosis by gonadal hormones under acute and chronic neurodegenerative conditions are still not fully clarified.

Endocrine and metabolic regulation of renal drug transporters.

Renal xenobiotic transporters are important determinants of urinary secretion and reabsorption of chemicals. In addition to glomerular filtration, these processes are key to the overall renal clearance of a diverse array of drugs and toxins. Alterations in kidney transporter levels and function can influence the efficacy and toxicity of chemicals. Studies in experimental animals have revealed distinct patterns of renal transporter expression in response to sex hormones, pregnancy, and growth hormone. Likewise, a number of disease states including diabetes, obesity, and cholestasis alter the expression of kidney transporters. The goal of this review is to provide an overview of the major xenobiotic transporters expressed in the kidneys and an understanding of metabolic conditions and hormonal factors that regulate their expression and function.